Using Drosophila to Study Mental Retardation in Humans
Overview: Drosophila melanogaster have long been a popular invertebrate for studying human genetic disorders. Despite the drosophila genome being comprised of fewer genes than that of humans (16,000-17,000 genes distributed among 4 pairs of chromosomes, while the human genome consists of around 27,000 genes on 23 pairs of chromosomes), 75% of all human disease genes can be matched on the drosophila genome. The latter makes this tiny fruit fly a valuable and inexpensive means for manipulating and studying genes that have been identified as causing genetic defects in humans. One such genetic disorder for which drosophila can be employed is Fragile X Syndrome, which is responsible for many forms of mental retardation, and is the leading known cause of autism. Fragile X is caused by the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development. The syndrome inflicts 1 in every 2,500 human males and 1 in every 8,000 females, and is characterized by intellectual disabilities, as well as specific phenotypic traits, like an elongated face and protruding ears. While no effective drug therapy currently exists for treating those with Fragile X (there is no way to reverse the functional loss of FMR1), studying the expression of the gene in drosophila and having the ability to manipulate the drosophila genome in the lab has provided essential information about the syndrome and how it might be thwarted and treated in the future. Genetic Study and Drosophila: The Case of Fragile X Syndrome Drosophila are primarily useful for studying Fragile X because they possess an FMR1 (often called dFMR1, with "d" standing for drosophila) gene that is homologous to human FMR1. The absence of dFMR1 function in Drosophila larvae causes neuromuscular junction neurons and dendrites of larval sensory neurons to exhibit an "increase in branching and neuronal complexity (Emory University study)," which is characteristic of what occurs in humans in the absence of FMR1. These abnormalities, caused by the absence of FMR1 expression, are what cause some of the telltale symptoms of mental retardation, such as decreased attention span and scattered and slow brain and motor functioning. As stated by Queensland Brain Institute researcher Bart van Alphen in his study of Fragile X Syndrome drosophila: "dFMR1 mutants have some similar behavioral impairments as FXS humans or mice. For example, they are unable to maintain a normal circadian rhythm in constant darkness, and exhibit erratic patterns of locomotor activity. Additionally, dFMR1 mutants are also impaired in higher order behaviors such as immediate recall memory, short term memory and longterm memory and social behavior." As is apparent, there is a direct correlation between the symtomss experienced by both humans and fruit flies when the FMR1 gene is not expressed. Using Drosophila to Test Potential Therapies to Reduce Cases of Fragile X Syndrome: It is believed that lacking FMR1 impairs learning and memory through regulation of protein synthesis at synapses in the brain, and that excessive stimulation of neurons by the neurotransmitter glutamate is a primary reason for brain dysfunction. In other words, being devoid of FMR1 causes over-firing of glutamate, which in turn causes symptoms of mental retardation. To study this "glutamate theory," Emory scientists used a Drosophila model lacking the FMR1 gene. When FMR1-deficient fly embryos were given food containing increased levels of glutamate, they died during development, "which is consistent with the theory that the loss of FMR1 results in excess glutamate signaling." To study this theory further, and to discern a possible treatment, the Emory scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. Each well also contained one compound from a library of 2,000 drugs deemed as viable treatment options. Using this screening method, the scientists uncovered nine drugs (none specified in the study) that reversed the lethal effects of glutamate in drosophila, which could mean the same may eventually be possible in humans. As stated by lead study author Dr. Stephen Warren of Emory University, "Our discovery of glutamate toxicity in the Drosophila model of fragile X syndrome allowed us to develop this new screen for potential drug targets. We believe this is the first chemical genetic screen for fragile X syndrome, and it highlights the general potential of Drosophila screens for drug development." Thus, the use of drosophila to study a wide array of human genetic disorders and diseases is quite prolific, and the recent findings here may eventually potentiate a treatment for humans with Fragile X and other forms of mental retardation. References: Alphen, Bart Van et al. "Drosophila Strategies to Study Psychiatric Disorders." Brain Research Bulletin, 2011. Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia Chang, Shuang. "Drosophila Drug Screening for Fragile X." Science DailyScience Daily, March 2008. Lowth, Aimee et all. "Psychiatric Drugs and the Brain." Neuroscience Fundamentals, 2013. Santos, AR. "Learning and Behavioral Deficits Associated with Fragile X Syndrome." PubMed. October, 2014.